An estimated 3% of the world's population is infected with the hepatitis C virus. The World Health Organization estimates that 150 million people are chronically infected worldwide. Of those exposed to HCV, 80% to 85% become chronically infected, at least 30% develop cirrhosis of the liver, and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will spontaneously clear HCV.
HCV is an enveloped, single-stranded RNA virus. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized. The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication; and virion assembly and release. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus.
There are several proteins in hepatitis C that have been targeted for drug therapy. NS5A is a zinc-binding proline rich hydrophilic phosphoprotein with no inherent enzymatic activity, which can be inhibited with certain non-nucleotide compounds. NS5B is a key enzyme which plays the major role in replicating HCV viral RNA using a viral positive RNA strand as a template, which has been inhibited with synthetic nucleoside derivatives. NS2-3 protease is an enzyme responsible for proteolytic cleavage between NS2 and NS3, which are non-structural proteins. NS3 protease is responsible for the cleavage of the non-structural protein downstream. RNA helicase uses ATP hydrolysis to unwind RNA.
Sofosbuvir (Sovaldi, see structure below) is a nucleoside phosphoramidate NS5B inhibitor approved in December 2013 for the treatment of HCV. The approved labeling recommends the following regimens: (i) for genotypes 2 and 3 a 400 mg once a day oral tablet in combination with ribavirin and (ii) for genotypes 1 and 4 a 400 mg once a day oral tablet (triple combination therapy) with ribavirin and pegylated interferon. The sofosbuvir treatment lasts 12 weeks for genotypes 1, 2 and 4 and 24 weeks for genotype 3. Sofosbuvir can also be used with ribavirin for the treatment of chronic hepatitis C patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation to prevent post-transplant HCV infection. The FDA granted Sovaldi Priority Review and Breakthrough Therapy designation based on data from several large clinical trials that indicated a sustained viral response (SVR) of twelve weeks in 50-90 percent of the trial participants. Patients who achieve “SVR12” are often considered cured.

Alios BioPharma, Inc. licensed ALS-2200 to Vertex Pharmaceuticals Inc. for hepatitis C treatment development in June 2011. ALS-2200 is a mixture of diastereomers at a chiral phosphorus stereocenter. A single diastereomer, VX-135, is being developed by Vertex, and is currently in Phase II clinical trials. While the companies have not disclosed the chemical structure of VX-135, they have said that it is a uridine nucleotide analog prodrug, and an NS5B inhibitor. In 2013, the FDA placed VX-135 on partial clinical hold after three patients receiving high dosages of VX-135 showed liver toxicity. Lowering the dose of a nucleotide inhibitor to avoid toxicity can sometimes also compromise or lower efficacy. Vertex announced in January 2014 that VX-135 in combination with daclastavir (Bristol-Myers Squibb NS5A inhibitor) had completed a Phase 2a trial. In an intent-to-treat analysis, the sustained viral response rate four weeks after completion of treatment (SVR4) was 83% (10 of 12) in treatment-naïve genotype 1 infected individuals who received 200 mg VX-135 in combination with daclatasvir. One patient exhibited a serious adverse event of vomiting/nausea. The eleven remaining patients completed 12 weeks of treatment, for a completion of treatment rate (SVR4) of 91%.
Idenix Pharmaceuticals Inc. is developing IDX21437 for the treatment of hepatitis C, which is a uridine nucleotide prodrug NS5B inhibitor. The details of the chemical structure have not been released to date. In April 2014, Idenix announced that once-daily 300 mg IDX21437 for seven days led to a mean maximum reduction in viral load of 4.2-4.3 log 10 IU/mL in 18 treatment naïve patients with genotype 1, 2 or 3.
Despite progress in the area of hepatitis C treatment, there have also been a number of difficult setbacks. BMS-986094, a guanosine-based phosphoramidate for hepatitis C was pulled from clinical trials after the death of a patient due to heart failure in August 2012. BMS thereafter announced in 2013 that it was exiting the hepatitis C research area. Following the BMS drug withdrawal, Idenix Pharmaceuticals's similar NS5B inhibitor, IDX 19368, which shares the same active metabolite, BMS-986094, was placed on clinical hold and ultimately discontinued. This followed the previous clinical hold and discontinuation of development of the nucleotide prodrug IDX184 for the same indication.
It is known that effective treatment against hepatitis C includes combination therapy, due to the onset of viral resistance during monotherapy. Given the documented challenges of developing optimal hepatitis C agents, and the fact that multiple optimal agents are required for effective therapy, there is a strong need for additional hepatitis C agents.